Reviews & Analysis

A new potential breast cancer oncogene, ZNF703, has been identified in the chromosomal region 8p12 in humans, which is commonly amplified in an aggressive subtype of breast cancer. ZNF703 is a transcriptional repressor and regulates many genes that are involved in multiple aspects of the cancer phenotype, such as increased proliferation, invasion and an altered balance of progenitor stem cells.

Brain injury, subarachnoid hemorrhage and the subsequent delayed ischemic stroke show spreading depolarization of neurons in the tissue at risk, where it leads to spreading ischemia, vasoconstriction and brain electrical silencing, exacerbating damage and thwarting recovery. Jens Dreier reviews the underlying molecular mechanisms and the potential use for clinical diagnosis and therapies aimed at blocking spreading depolarization and boosting vasodilation to treat neurological disease.

Mitochondrial fission-fusion and trafficking are altered in the fatal neurodegenerative disorder Huntington's disease. Huntingtin is now shown to function directly in these processes by binding the mitochondrial fission factor dynamin-related protein-1 (DRP1). Mutant huntingtin binds more tightly to DRP1, leading to increased mitochondrial fission and neuronal death, highlighting DRP1 as a potential therapeutic target in Huntington's disease (pages 377–382).

Although the rapid development of drug resistance is a known problem with targeted cancer therapies, recent studies have uncovered other surprises with RAF kinase inhibitors. These drugs can paradoxically activate downstream ERK signaling in some settings, with important implications for their clinical use.

Neuroblastoma is a fatal childhood cancer, but lack of knowledge about the underlying causative genes has hampered the development of effective therapies. The identification of anaplastic lymphoma kinase (ALK) mutations as drivers of neuroblastoma has indicated that targeted therapy with ALK inhibitors might be a valuable strategy in the fight against this lethal cancer.

Therapeutic resistance is a key roadblock to effective cancer treatment and can occur through various mechanisms. A recent study characterized a previously unknown, reversible mechanism of drug resistance mediated by an altered chromatin state, suggesting that cancer cell populations can use a dynamic strategy to ensure their survival when challenged by therapeutic intervention.

A continuing quest in clinical oncology is to effectively eliminate tumors without major side effects. But drugs rationally tailored against specific tumors and predictive markers for patient selection are very limited, and their identification is challenging. A phase 1 study has provided proof of concept for the use of PARP inhibitors in tumors from individuals carrying BRCA mutations—a remarkable success in rational drug design and translational research.

X-box–binding protein-1 (XBP-1) increases insulin sensitivity by activating endoplasmic reticulum capacity during feeding to control glucose homeostasis, a function severely impaired in obesity. But XBP-1 can also increase glucose tolerance in obese and diabetic mice by blocking gluconeogenesis, independent of its effect on insulin sensitivity, opening new avenues for type 2 diabetes therapies (pages 356–365).

Inflammation is an important component of the tumor microenvironment; however, the mechanisms through which immune cells might promote tumorigenesis are unclear. A recent study indicates that B cells and antibodies have a key role in orchestrating macrophage-driven, tumor-promoting inflammation, suggesting that modulating the pathways involved might be of therapeutic benefit in cancers driven by chronic inflammation.

Recently characterized IDH1 and IDH2 mutations in leukemia and glioblastoma have introduced a fascinating cancer-specific role for metabolic genes essential to cellular respiration. Studies also link aberrant IDH1 and IDH2 activity to an altered metabolite profile, an observation that may have broad implications for both cancer epigenetics and clinical management of disease.

A microRNA decreases the expression of the adhesion molecule CD44 in prostate cancer stem cells (CSCs), blocking tumor growth and metastasis in mice (pages 211–215). Systemic delivery of this negative regulator may open new avenues for targeting CSCs to halt cancer.

Chronic inflammation is associated with obesity, but the pathways that mediate this phenomenon are not fully characterized. The nucleotide-binding domain, leucine-rich–containing family, pyrin domain–containing-3 (Nlrp3) inflammasome functions as a sensor to detect danger signals and induce downstream inflammatory signaling that contributes to obesity-associated conditions such as insulin resistance (pages 179–188).

Triglyceride-rich lipoproteins (TRLs) transport lipid calories to tissues that need energy, but TRLs can also contribute to obesity and vascular disease. A newly discovered pathway shows how cold exposure increases the uptake and combustion of TRLs by brown adipose tissue, thereby correcting harmful hyperlipidemias (pages 200–205).

Hyperglycemia is a risk factor for poor outcomes after intracerebral hemorrhage (ICH), but what drives its effects on ICH is unknown. A new study shows that plasma kallikrein mediates hyperglycemia-induced hematoma expansion in rats and mice with ICH by inhibiting blood platelets (pages 206–210).